Organophosphorous compounds are used in chemical weapons, including nerve agents such as methylphosphonofluoridic acid 1-methyl-ethyl ester (sarin), pinacolyl methylphosphono fluoridate (soman), and methylphosphonothioic acid S-2-bis(1-methylethyl)amino!ethyl!O-ethyl ester (VX), and in insecticides such as phosphoric acid diethyl 4-nitrophenyl ester (paraoxon), diethyl-p-nitrophenyl monothiophosphate (parathion) and phosphorothioic acid O-(3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl) O,O-diethyl ester (coumaphos). Exposure to even small amounts of a nerve agent can be fatal. In humans, the mechanism of organophosphate poisoning involves reaction with a serine hydroxyl group in the active site of a key enzyme acetylcholinesterase ("AChE") producing an inactive and phosphorylated enzyme. The classical therapeutic approach for reactivating an inactive phosphorylated enzyme is treatment with nucleophilic oximes, which react with phosphorylated AChE and release the active enzyme. See I. B. Wilson; S. A. Ginsburg Biochem. Biophys. Acta, 1955, 18, 168-170.
Oximes such as pyridinium aldoxime methochloride ("PAM") have been used to treat the actions of some organophosphates, however, they are not effective for other organophosphates such as soman (J. H. Fleisher et al. J. Pharmacol. Exp. Ther. 1967, 156, 345-351). Derivatives of 1-methylpyridinium-aldoxime iodides have also been used as reactivators of AChE (E. J. Poziomek et al. J. Org. Chem. 1958, 23, 714-717). Such oximes are structurally analogous to the AChE inhibitor 9-amino-1,2,3,4-tetrahydroacridine ("THA"), which has been shown to bind to both a catalytic binding site and a peripheral binding site of AChE (See FIG. 2) (Y.-P. Pang et al. J. Biol. Chem. 1996, 271, 23646-23649).
The effectiveness of an oxime AChE reactivator depends on the intrinsic equilibrium constant for the equilibrium illustrated in FIG. 1. Reactivation is effective only when enzyme dephosphorylation is faster than oxime dephosphorylation. There is currently a need for effective reactivators of AChE.